Medical Specialties Commons^™

Pathophysiology In Brain Arteriovenous Malformations: Focus On Endothelial Dysfunctions And Endothelial-To-Mesenchymal Transition, Jae Yeong Jeong, Adrian E Bafor, Bridger H Freeman, Peng R Chen, Eun S Park, Eunhee Kim

Faculty, Staff and Student Publications

Brain arteriovenous malformations (bAVMs) substantially increase the risk for intracerebral hemorrhage (ICH), which is associated with significant morbidity and mortality. However, the treatment options for bAVMs are severely limited, primarily relying on invasive methods that carry their own risks for intraoperative hemorrhage or even death. Currently, there are no pharmaceutical agents shown to treat this condition, primarily due to a poor understanding of bAVM pathophysiology. For the last decade, bAVM research has made significant advances, including the identification of novel genetic mutations and relevant signaling in bAVM development. However, bAVM pathophysiology is still largely unclear. Further investigation is required to …

Correction: Multilocus Pathogenic Variants Contribute To Intrafamilial Clinical Heterogeneity: A Retrospective Study Of Sibling Pairs With Neurodevelopmental Disorders, Tugce Bozkurt-Yozgatli, Davut Pehlivan, Richard A Gibbs, Ugur Sezerman, Jennifer E Posey, James R Lupski, Zeynep Coban-Akdemir

Faculty, Staff and Students Publications

No abstract provided.

A Machine Learning Model For Risk Stratification Of Postdiagnosis Diabetic Ketoacidosis Hospitalization In Pediatric Type 1 Diabetes: Retrospective Study, Devika Subramanian, Rona Sonabend, Ila Singh

Faculty, Staff and Students Publications

BACKGROUND: Diabetic ketoacidosis (DKA) is the leading cause of morbidity and mortality in pediatric type 1 diabetes (T1D), occurring in approximately 20% of patients, with an economic cost of $5.1 billion/year in the United States. Despite multiple risk factors for postdiagnosis DKA, there is still a need for explainable, clinic-ready models that accurately predict DKA hospitalization in established patients with pediatric T1D.

OBJECTIVE: We aimed to develop an interpretable machine learning model to predict the risk of postdiagnosis DKA hospitalization in children with T1D using routinely collected time-series of electronic health record (EHR) data.

METHODS: We conducted a retrospective case-control …

Bispecific Antibodies And Autologous Chimeric Antigen Receptor T Cell Therapies For Treatment Of Hematological Malignancies, Samer Al Hadidi, Helen E Heslop, Malcolm K Brenner, Masataka Suzuki

Faculty, Staff and Students Publications

In recent years, the therapeutic landscape for hematological malignancies has markedly advanced, particularly since the inaugural approval of autologous chimeric antigen receptor T cell (CAR-T) therapy in 2017 for relapsed/refractory acute lymphoblastic leukemia (ALL). Autologous CAR-T therapy involves the genetic modification of a patient's T cells to specifically identify and attack cancer cells, while bispecific antibodies (BsAbs) function by binding to both cancer cells and immune cells simultaneously, thereby triggering an immune response against the tumor. The subsequent approval of various CAR-T therapies and BsAbs have revolutionized the treatment of multiple hematological malignancies, highlighting high response rates and a subset …

Comparative Plan Analysis: Helical Tomotherapy Vs. Linac Vmat For Lower Extremity Sarcomas, Marie E. Dibona

Masters Projects

Abstract

Introduction

Soft tissue sarcomas (STS) affect about 13,500 people annually in the United States, and those in the lower extremities present unique challenges in radiation therapy due to the wide variability in tumor sizes, sometimes exceeding 30cm. Traditional treatment involves C-Arm linear accelerators using Volumetric Modulated Radiation Therapy (VMAT), which provides precise targeting while sparing nearby organs. Helical Tomotherapy (HT) is another option, delivering radiation in a helical pattern with a binary MLC for a uniform dose distribution. However, no studies have compared VMAT and HT for lower extremity sarcomas of different sizes. This study aims to compare these …

Pkd1 Mutant Clones Within Cirrhotic Livers Inhibit Steatohepatitis Without Promoting Cancer, Min Zhu, Yunguan Wang, Tianshi Lu, Jason Guo, Lin Li, Meng-Hsiung Hsieh, Purva Gopal, Yi Han, Naoto Fujiwara, Darren P Wallace, Alan S L Yu, Xiangyi Fang, Crystal Ransom, Sara Verschleisser, David Hsiehchen, Yujin Hoshida, Amit G Singal, Adam Yopp, Tao Wang, Hao Zhu

Faculty, Staff and Student Publications

Somatic mutations in non-malignant tissues are selected for because they confer increased clonal fitness. However, it is uncertain whether these clones can benefit organ health. Here, ultra-deep targeted sequencing of 150 liver samples from 30 chronic liver disease patients revealed recurrent somatic mutations. PKD1 mutations were observed in 30% of patients, whereas they were only detected in 1.3% of hepatocellular carcinomas (HCCs). To interrogate tumor suppressor functionality, we perturbed PKD1 in two HCC cell lines and six in vivo models, in some cases showing that PKD1 loss protected against HCC, but in most cases showing no impact. However, Pkd1 haploinsufficiency …

Whole Genome Sequencing Based Analysis Of Inflammation Biomarkers In The Trans-Omics For Precision Medicine (Topmed) Consortium, Min-Zhi Jiang, Sheila M Gaynor, Xihao Li, Eric Van Buren, Adrienne Stilp, Erin Buth, Fei Fei Wang, Regina Manansala, Stephanie M Gogarten, Zilin Li, Linda M Polfus, Shabnam Salimi, Joshua C Bis, Nathan Pankratz, Lisa R Yanek, Peter Durda, Russell P Tracy, Stephen S Rich, Jerome I Rotter, Braxton D Mitchell, Joshua P Lewis, Bruce M Psaty, Katherine A Pratte, Edwin K Silverman, Robert C Kaplan, Christy Avery, Kari E North, Rasika A Mathias, Nauder Faraday, Honghuang Lin, Biqi Wang, April P Carson, Arnita F Norwood, Richard A Gibbs, Charles Kooperberg, Jessica Lundin, Ulrike Peters, Josée Dupuis, Lifang Hou, Myriam Fornage, Emelia J Benjamin, Alexander P Reiner, Russell P Bowler, Xihong Lin, Paul L Auer, Laura M Raffield, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Topmed Inflammation Working Group

Faculty, Staff and Student Publications

Inflammation biomarkers can provide valuable insight into the role of inflammatory processes in many diseases and conditions. Sequencing based analyses of such biomarkers can also serve as an exemplar of the genetic architecture of quantitative traits. To evaluate the biological insight, which can be provided by a multi-ancestry, whole-genome based association study, we performed a comprehensive analysis of 21 inflammation biomarkers from up to 38 465 individuals with whole-genome sequencing from the Trans-Omics for Precision Medicine (TOPMed) program (with varying sample size by trait, where the minimum sample size was n = 737 for MMP-1). We identified 22 distinct single-variant …

Identification And Characterization Of A Skin Microbiome On Caenorhabditis Elegans Suggests Environmental Microbes Confer Cuticle Protection, Nadia B Haghani, Robert H Lampe, Buck S Samuel, Sreekanth H Chalasani, Molly A Matty

Faculty, Staff and Students Publications

In the wild, C. elegans are emersed in environments teeming with a veritable menagerie of microorganisms. The C. elegans cuticular surface serves as a barrier and first point of contact with their microbial environments. In this study, we identify microbes from C. elegans natural habitats that associate with its cuticle, constituting a simple “skin microbiome.” We rear our animals on a modified CeMbio, mCeMbio, a consortium of ecologically relevant microbes. We first combine standard microbiological methods with an adapted micro skin-swabbing tool to describe the skin-resident bacteria on the C. elegans surface. Furthermore, we conduct 16S rRNA gene sequencing studies …

Diagnostic Utility Of Dna Methylation Analysis In Genetically Unsolved Pediatric Epilepsies And Chd2 Episignature Refinement, Christy W Laflamme, Cassandra Rastin, Soham Sengupta, Helen E Pennington, Sophie J Russ-Hall, Amy L Schneider, Emily S Bonkowski, Edith P Almanza Fuerte, Talia J Allan, Miranda Perez-Galey Zalusky, Joy Goffena, Sophia B Gibson, Denis M Nyaga, Nico Lieffering, Malavika Hebbar, Emily V Walker, Daniel Darnell, Scott R Olsen, Pandurang Kolekar, Mohamed Nadhir Djekidel, Wojciech Rosikiewicz, Haley Mcconkey, Jennifer Kerkhof, Michael A Levy, Raissa Relator, Dorit Lev, Tally Lerman-Sagie, Kristen L Park, Marielle Alders, Gerarda Cappuccio, Nicolas Chatron, Leigh Demain, David Genevieve, Gaetan Lesca, Tony Roscioli, Damien Sanlaville, Matthew L Tedder, Sachin Gupta, Elizabeth A Jones, Monika Weisz-Hubshman, Shamika Ketkar, Hongzheng Dai, Kim C Worley, Jill A Rosenfeld, Hsiao-Tuan Chao, Undiagnosed Diseases Network, Geoffrey Neale, Gemma L Carvill, University Of Washington Center For Rare Disease Research, Zhaoming Wang, Samuel F Berkovic, Lynette G Sadleir, Danny E Miller, Ingrid E Scheffer, Bekim Sadikovic, Heather C Mefford

Faculty, Staff and Students Publications

Sequence-based genetic testing identifies causative variants in ~ 50% of individuals with developmental and epileptic encephalopathies (DEEs). Aberrant changes in DNA methylation are implicated in various neurodevelopmental disorders but remain unstudied in DEEs. We interrogate the diagnostic utility of genome-wide DNA methylation array analysis on peripheral blood samples from 582 individuals with genetically unsolved DEEs. We identify rare differentially methylated regions (DMRs) and explanatory episignatures to uncover causative and candidate genetic etiologies in 12 individuals. Using long-read sequencing, we identify DNA variants underlying rare DMRs, including one balanced translocation, three CG-rich repeat expansions, and four copy number variants. We also …

An Interesting Case Of Wunderlich Syndrome And Page Kidney, Megan Worthington, Nicholaus Monsma, Raj Pyne

Advances in Clinical Medical Research and Healthcare Delivery

We present a case of Wunderlich Syndrome and Page Kidney, a rarely reported combination. Wunderlich Syndrome, characterized by spontaneous renal hemorrhage without a history of trauma, is typically associated with Lenk’s triad of flank pain, mass, and hypovolemia. Page Kidney induced hypertension, a rare condition resulting from external renal compression associated with renin-mediated mechanisms. Our case demonstrates the importance in quick recognition and treatment as blood pressure changes can be fast and dramatic. Our case also has the added dimension of renin measurements. After the patients hypertension developed, his initial renin levels were within normal range, but they later showed …

Disability In Cluster Headache Is More Than Attack Frequency – Results From And Validation Of The English Version Of The Cluster Headache Impact Questionnaire (Chiq), Katharina Kamm, Andreas Straube, Mark Burish, Ruth Ruscheweyh

Faculty, Staff and Student Publications

BACKGROUND: Cluster headache (CH) is associated with high disability. The Cluster Headache Impact Questionnaire (CHIQ) is a short, disease-specific disability questionnaire first developed and validated in German. Here, we validated the English version of this questionnaire.

METHODS: The CHIQ was assessed together with nonspecific headache-related disability questionnaires in CH patients from a tertiary headache center and an American self-help group.

RESULTS: 155 active episodic and chronic CH patients were included. The CHIQ showed good internal consistency (Cronbach's α = 0.91) and test-retest reliability (ICC = 0.93, n = 44). Factor analysis identified a single factor. Convergent validity was shown by …

Adjuvant External Beam Radiotherapy Combined With Brachytherapy For Intermediate-Risk Cervical Cancer, Nuria Agusti, David Viveros-Carreño, Alexander Melamed, Rene Pareja, Alexa Kanbergs, Chi-Fang Wu, Roni Nitecki, Lauren Colbert, Jose Alejandro Rauh-Hain

Faculty, Staff and Student Publications

Objective: Patients with intermediate-risk cervical cancer receive external beam radiotherapy (EBRT) as adjuvant treatment. It is commonly administered with brachytherapy without proven benefits. Therefore, we evaluated the frequency of brachytherapy use, the doses for EBRT administered alone or with brachytherapy, and the overall survival impact of brachytherapy in patients with intermediate-risk, early-stage cervical cancer.

Methods: This retrospective cohort study was performed using data collected from the National Cancer Database. Patients diagnosed with cervical cancer from 2004 to 2019 who underwent a radical hysterectomy and lymph node staging and had disease limited to the cervix but with tumors larger than 4 …

The Oncolytic Adenovirus Delta-24-Rgd In Combination With Onc201 Induces A Potent Antitumor Response In Pediatric High-Grade And Diffuse Midline Glioma Models, Daniel De La Nava, Iker Ausejo-Mauleon, Virginia Laspidea, Marisol Gonzalez-Huarriz, Andrea Lacalle, Noelia Casares, Marta Zalacain, Lucía Marrodan, Marc García-Moure, Maria C Ochoa, Antonio Carlos Tallon-Cobos, Reyes Hernandez-Osuna, Javier Marco-Sanz, Laasya Dhandapani, Irati Hervás-Corpión, Oren J Becher, Javad Nazarian, Sabine Mueller, Timothy N Phoenix, Jasper Van Der Lugt, Mikel Hernaez, Elizabeth Guruceaga, Carl Koschmann, Sriram Venneti, Joshua E Allen, Matthew D Dun, Juan Fueyo, Candelaria Gomez-Manzano, Jaime Gallego Perez-Larraya, Ana Patiño-García, Sara Labiano, Marta M Alonso

Faculty, Staff and Student Publications

BACKGROUND: Pediatric high-grade gliomas (pHGGs), including diffuse midline gliomas (DMGs), are aggressive pediatric tumors with one of the poorest prognoses. Delta-24-RGD and ONC201 have shown promising efficacy as single agents for these tumors. However, the combination of both agents has not been evaluated.

METHODS: The production of functional viruses was assessed by immunoblotting and replication assays. The antitumor effect was evaluated in a panel of human and murine pHGG and DMG cell lines. RNAseq, the seahorse stress test, mitochondrial DNA content, and γH2A.X immunofluorescence were used to perform mechanistic studies. Mouse models of both diseases were used to assess the …

Tumour-Intrinsic Endomembrane Trafficking By Arf6 Shapes An Immunosuppressive Microenvironment That Drives Melanomagenesis And Response To Checkpoint Blockade Therapy, Yinshen Wee, Junhua Wang, Emily C Wilson, Coulson P Rich, Aaron Rogers, Zongzhong Tong, Evelyn Degroot, Y N Vashisht Gopal, Michael A Davies, H Atakan Ekiz, Joshua K H Tay, Chris Stubben, Kenneth M Boucher, Juan M Oviedo, Keke C Fairfax, Matthew A Williams, Sheri L Holmen, Roger K Wolff, Allie H Grossmann

Faculty, Staff and Student Publications

Tumour-host immune interactions lead to complex changes in the tumour microenvironment (TME), impacting progression, metastasis and response to therapy. While it is clear that cancer cells can have the capacity to alter immune landscapes, our understanding of this process is incomplete. Herein we show that endocytic trafficking at the plasma membrane, mediated by the small GTPase ARF6, enables melanoma cells to impose an immunosuppressive TME that accelerates tumour development. This ARF6-dependent TME is vulnerable to immune checkpoint blockade therapy (ICB) but in murine melanoma, loss of Arf6 causes resistance to ICB. Likewise, downregulation of ARF6 in patient tumours correlates with …

Non-Receptor Tyrosine Kinases: Their Structure And Mechanistic Role In Tumor Progression And Resistance, Abdulaziz M. Eshaq, Thomas W. Flanagan, Sofie Yasmin Hassan, Sara A. Al Asheikh, Waleed A. Al-Amoudi, Simeon Santourlidis, Sarah Lilly Hassan, Maryam O. Alamodi, Marcelo L. Bendhack, Mohammed O. Alamodi, Youssef Haikel, Mossad Megahed, Mohamed Hassan

School of Graduate Studies Faculty Publications

Protein tyrosine kinases (PTKs) function as key molecules in the signaling pathways in addition to their impact as a therapeutic target for the treatment of many human diseases, including cancer. PTKs are characterized by their ability to phosphorylate serine, threonine, or tyrosine residues and can thereby rapidly and reversibly alter the function of their protein substrates in the form of significant changes in protein confirmation and affinity for their interaction with protein partners to drive cellular functions under normal and pathological conditions. PTKs are classified into two groups: one of which represents tyrosine kinases, while the other one includes the …

Translational Modeling-Based Evidence For Enhanced Efficacy Of Standard-Of-Care Drugs In Combination With Anti-Microrna-155 In Non-Small-Cell Lung Cancer, Prashant Dogra, Vrushaly Shinglot, Javier Ruiz-Ramírez, Joseph Cave, Joseph D Butner, Carmine Schiavone, Dan G Duda, Ahmed O Kaseb, Caroline Chung, Eugene J Koay, Vittorio Cristini, Bulent Ozpolat, George A Calin, Zhihui Wang

Faculty, Staff and Student Publications

BACKGROUND: Elevated microRNA-155 (miR-155) expression in non-small-cell lung cancer (NSCLC) promotes cisplatin resistance and negatively impacts treatment outcomes. However, miR-155 can also boost anti-tumor immunity by suppressing PD-L1 expression. Therapeutic targeting of miR-155 through its antagonist, anti-miR-155, has proven challenging due to its dual molecular effects.

METHODS: We developed a multiscale mechanistic model, calibrated with in vivo data and then extrapolated to humans, to investigate the therapeutic effects of nanoparticle-delivered anti-miR-155 in NSCLC, alone or in combination with standard-of-care drugs.

RESULTS: Model simulations and analyses of the clinical scenario revealed that monotherapy with anti-miR-155 at a dose of 2.5 mg/kg …

Kinesin Facilitates Phenotypic Targeting Of Therapeutic Resistance In Advanced Prostate Cancer, Maddison Archer, Diane Begemann, Edgar Gonzalez-Kozlova, Prerna R Nepali, Estefania Labanca, Peter Shepherd, Navneet Dogra, Nora Navone, Natasha Kyprianou

Faculty, Staff and Student Publications

Understanding the mechanisms underlying resistance is critical to improving therapeutic outcomes in patients with metastatic castration-resistant prostate cancer. Previous work showed that dynamic interconversions between epithelial-mesenchymal transition to mesenchymal-epithelial transition defines the phenotypic landscape of prostate tumors, as a potential driver of the emergence of therapeutic resistance. In this study, we use in vitro and in vivo preclinical MDA PCa patient-derived xenograft models of resistant human prostate cancer to determine molecular mechanisms of cross-resistance between antiandrogen therapy and taxane chemotherapy, underlying the therapeutically resistant phenotype. Transcriptomic profiling revealed that resistant and sensitive prostate cancer C4-2B cells have a unique differential …

Brca1-Mediated Dual Regulation Of Ferroptosis Exposes A Vulnerability To Gpx4 And Parp Co-Inhibition In Brca1-Deficient Cancers, Guang Lei, Chao Mao, Amber D Horbath, Yuelong Yan, Shirong Cai, Jun Yao, Yan Jiang, Mingchuang Sun, Xiaoguang Liu, Jun Cheng, Zhihao Xu, Hyemin Lee, Qidong Li, Zhengze Lu, Li Zhuang, Mei-Kuang Chen, Anagha Alapati, Timothy A Yap, Mien-Chie Hung, Mingjian James You, Helen Piwnica-Worms, Boyi Gan

Faculty, Staff and Student Publications

Resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) limits the therapeutic efficacy of PARP inhibition in treating breast cancer susceptibility gene 1 (BRCA1)-deficient cancers. Here we reveal that BRCA1 has a dual role in regulating ferroptosis. BRCA1 promotes the transcription of voltage-dependent anion channel 3 (VDAC3) and glutathione peroxidase 4 (GPX4); consequently, BRCA1 deficiency promotes cellular resistance to erastin-induced ferroptosis but sensitizes cancer cells to ferroptosis induced by GPX4 inhibitors (GPX4i). In addition, nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and defective GPX4 induction unleash potent ferroptosis in BRCA1-deficient cancer cells upon PARPi and GPX4i …

Rosiglitazone And Trametinib Exhibit Potent Anti-Tumor Activity In A Mouse Model Of Muscle Invasive Bladder Cancer, Sakina A Plumber, Tiffany Tate, Hikmat Al-Ahmadie, Xiao Chen, Woonyoung Choi, Merve Basar, Chao Lu, Aaron Viny, Ekatherina Batourina, Jiaqi Li, Kristjan Gretarsson, Besmira Alija, Andrei Molotkov, Gregory Wiessner, Byron Hing Lung Lee, James Mckiernan, David J Mcconkey, Colin Dinney, Bogdan Czerniak, Cathy Lee Mendelsohn

Faculty, Staff and Student Publications

Muscle invasive bladder cancers (BCs) can be divided into 2 major subgroups-basal/squamous (BASQ) tumors and luminal tumors. Since Pparg has low or undetectable expression in BASQ tumors, we tested the effects of rosiglitazone, Pparg agonist, in a mouse model of BASQ BC. We find that rosiglitazone reduces proliferation while treatment with rosiglitazone plus trametinib, a MEK inhibitor, induces apoptosis and reduces tumor volume by 91% after 1 month. Rosiglitazone and trametinib also induce a shift from BASQ to luminal differentiation in tumors, which our analysis suggests is mediated by retinoid signaling, a pathway known to drive the luminal differentiation program. …

Gastrocnemius Electrical Stimulation Increases Ankle Dorsiflexion Strength In Patients With Post-Acute Sequelae Of Sars-Cov-2 (Pasc): A Double-Blind Randomized Controlled Trial, Myeounggon Lee, Alejandro Zulbaran-Rojas, Miguel Bargas-Ochoa, Bernardo Martinez-Leal, Rasha Bara, Areli Flores-Camargo, M G Finco, Ram Kinker Mishra, Jaewon Beom, Dipaben Modi, Fidaa Shaib, Bijan Najafi

Faculty, Staff and Students Publications

Post-Acute sequelae of SARS-CoV-2 (PASC) is a multisystem disorder causing persistent musculoskeletal deconditioning and reduced lower extremity strength. Electrical stimulation (E-Stim) to the gastrocnemius muscle can enhance strength outcomes by increasing the frequency of muscle fiber activation. We investigated its effect on individuals with PASC. Participants were randomized into intervention (IG) or control (CG) groups. The IG self-administered daily one-hour E-Stim to both their gastrocnemius muscles using a functional device over 4-week, while the CG used a sham device. Primary outcomes were ankle dorsiflexion strength assessed via dynamometry during maximum voluntary contractions, and gastrocnemius voluntary activation (GVA) via surface electromyography. …

Caspase-2 Is Essential For Proliferation And Self-Renewal Of Nucleophosmin-Mutated Acute Myeloid Leukemia, Dharaniya Sakthivel, Alexandra N Brown-Suedel, Karla E Lopez, Suruchi Salgar, Luiza E Coutinho, Francesca Keane, Shixia Huang, Kenneth Mc Sherry, Chloé I Charendoff, Kevin P Dunne, Dexter J Robichaux, Alexander Vargas-Hernández, Baochau Le, Crystal S Shin, Alexandre F Carisey, Marcin Poreba, Jonathan M Flanagan, Lisa Bouchier-Hayes

Faculty, Staff and Students Publications

Mutation in nucleophosmin (NPM1) causes relocalization of this normally nucleolar protein to the cytoplasm (NPM1c+). Despite NPM1 mutation being the most common driver mutation in cytogenetically normal adult acute myeloid leukemia (AML), the mechanisms of NPM1c+-induced leukemogenesis remain unclear. Caspase-2 is a proapoptotic protein activated by NPM1 in the nucleolus. Here, we show that caspase-2 is also activated by NPM1c+ in the cytoplasm and DNA damage–induced apoptosis is caspase-2 dependent in NPM1c+ but not in NPM1wt AML cells. Strikingly, in NPM1c+ cells, caspase-2 loss results in profound cell cycle arrest, differentiation, and down-regulation of stem cell pathways that regulate …

Lipid Droplet-Associated Hydrolase Mobilizes Stores Of Liver X Receptor Sterol Ligands And Protects Against Atherosclerosis, Young-Hwa Goo, Janeesh Plakkal Ayyappan, Francis D Cheeran, Sushant Bangru, Pradip K Saha, Paula Baar, Sabine Schulz, Todd A Lydic, Bernhard Spengler, Andreas H Wagner, Auinash Kalsotra, Vijay K Yechoor, Antoni Paul

Faculty, Staff and Students Publications

Foam cells in atheroma are engorged with lipid droplets (LDs) that contain esters of regulatory lipids whose metabolism remains poorly understood. LD-associated hydrolase (LDAH) has a lipase structure and high affinity for LDs of foam cells. Using knockout and transgenic mice of both sexes, here we show that LDAH inhibits atherosclerosis development and promotes stable lesion architectures. Broad and targeted lipidomic analyzes of primary macrophages and comparative lipid profiling of atheroma identified a broad impact of LDAH on esterified sterols, including natural liver X receptor (LXR) sterol ligands. Transcriptomic analyzes coupled with rescue experiments show that LDAH modulates the expression …

Znf397 Deficiency Triggers Tet2-Driven Lineage Plasticity And Ar-Targeted Therapy Resistance In Prostate Cancer, Yaru Xu, Yuqiu Yang, Zhaoning Wang, Martin Sjöström, Yuyin Jiang, Yitao Tang, Siyuan Cheng, Su Deng, Choushi Wang, Julisa Gonzalez, Nickolas A Johnson, Xiang Li, Xiaoling Li, Lauren A Metang, Atreyi Mukherji, Quanhui Xu, Carla R Tirado, Garrett Wainwright, Xinzhe Yu, Spencer Barnes, Mia Hofstad, Yu Chen, Hong Zhu, Ariella B Hanker, Ganesh V Raj, Guanghui Zhu, Housheng H He, Zhao Wang, Carlos L Arteaga, Han Liang, Felix Y Feng, Yunguan Wang, Tao Wang, Ping Mu

Faculty, Staff and Students Publications

Cancer cells exhibit phenotypical plasticity and epigenetic reprogramming that allows them to evade lineage-dependent targeted treatments by adopting lineage plasticity. The underlying mechanisms by which cancer cells exploit the epigenetic regulatory machinery to acquire lineage plasticity and therapy resistance remain poorly understood. We identified zinc finger protein 397 (ZNF397) as a bona fide coactivator of the androgen receptor (AR), essential for the transcriptional program governing AR-driven luminal lineage. ZNF397 deficiency facilitates the transition of cancer cell from an AR-driven luminal lineage to a ten-eleven translocation 2 (TET2)-driven lineage plastic state, ultimately promoting resistance to therapies inhibiting AR signaling. Intriguingly, our …

Parameter Estimation For Stroke Patients Using Brain Ct Perfusion Imaging With Deep Temporal Convolutional Neural Network, Shake Ibna Abir

Masters Theses & Specialist Projects

Acute ischemic stroke, caused by cerebral artery blockage, is a leading cause of long-term disability and mortality. Effective management relies on accurate, timely assessments from neuroimaging data. Computed tomography perfusion (CTP) imaging is crucial in evaluating stroke patients, offering detailed maps of cerebral perfusion to identify irreversibly damaged tissue and at-risk areas. This detailed assessment is essential for informed therapeutic decisions.

Key perfusion parameters derived from CTP imaging, including cerebral blood volume (CBV), cerebral blood flow (CBF), time to peak (TTP), and mean transit time (MTT), are crucial for understanding the extent and nature of cerebral ischemia, providing valuable insights …

Utilising Discriminant Function Analysis (Dfa) For Classifying Osteoarthritis (Oa) Patients And Volunteers Based On Biomarker Concentration, Laura Jane Coleman, John L Byrne, Stuart Edwards, Rosemary O'Hara

Faculty, Staff and Student Publications

Osteoarthritis (OA) is a degenerative joint disease characterised by the breakdown of cartilage, causing pain, stiffness, and limited movement. Early diagnosis is crucial for effective management but remains challenging due to non-specific early symptoms. This study explores the application of Discriminant Function Analysis (DFA) to classify OA patients and healthy volunteers based on biomarker concentrations of Interleukin-6 (IL-6), Tumour necrosis factor-alpha (TNF-α), and Myeloperoxidase (MPO). DFA was employed to analyse biomarker data from 86 participants (58 patients, 28 volunteers) to evaluate the discriminatory power of these biomarkers in predicting OA. Significant differences were observed in MPO and TNF-α levels between …

Institution-Wide Retreats Foster Organizational Learning And Action At A Comprehensive Cancer Center, Benjamin R Schrank, John A Fuller, Colleen M Gallagher, Van K Morris, Emma B Holliday, Kelly Merriman, Lynne Nguyen, Lou Weaver, Kelly Nelson, Elizabeth Chiao, Albert C Koong, Ernest Hawk, Shine Chang

Faculty, Staff and Student Publications

Providing safe and informed healthcare for sexual and gender minority (SGM) individuals with cancer is stymied by the lack of sexual orientation and gender identity (SOGI) data reliably available in health records and by insufficient training for staff. Approaches that support institutional learning, especially around sensitive topics, are essential for hospitals seeking to improve practices impacting patient safety and research. We engineered annual institutional retreats to identify and unify stakeholders, promote awareness of gaps and needs, identify initiatives, minimize redundant projects, and coordinate efforts that promote improvements in SGM cancer care, education, and research. The 2022 and 2023 retreats employed …

Poly(Adp-Ribose) Polymerase-1 Regulates Pyroptosis Independent Function Of Nlrp3 Inflammasome In Neutrophil Extracellular Trap Formation, Louis J Delinois, Atul Sharma, Ashwin K Ramesh, Laurel D Boatright, Qun Li, Rong Xu, Hongbo R Luo, Bibhuti B Mishra, Jyotika Sharma

Faculty, Staff and Student Publications

Neutrophil extracellular traps (NETs) function to control infectious agents as well as to propagate inflammatory response in a variety of disease conditions. DNA damage associated with chromatin decondensation and NACHT domain-leucine-rich repeat-and pyrin domain-containing protein 3 (NLRP3) inflammasome activation have emerged as crucial events in NET formation, but the link between the two processes is unknown. In this study, we demonstrate that poly(ADP-ribose) polymerase-1 (PARP-1), a key DNA repair enzyme, regulates NET formation triggered by NLRP3 inflammasome activation in neutrophils. Activation of mouse neutrophils with canonical NLRP3 stimulants LPS and nigericin induced NET formation, which was significantly abrogated by pharmacological …

Mechanism And Rational Combinations With Gp-2250, A Novel Oxathiazine Derivative, In Ovarian Cancer, Mark S Kim, Deanna Glassman, Katelyn F Handley, Adrian Lankenau Ahumada, Nicholas B Jennings, Emine Bayraktar, Katherine Foster, Robiya Joseph, Sanghoon Lee, Robert L Coleman, Anil K Sood

Faculty, Staff and Student Publications

BACKGROUND: GP-2250, a novel analog of taurultam (TRLT), has emerged as a potent anti-neoplastic drug; however, the mechanisms underlying its effects are not well understood. Here, we investigated the mechanism of action and the biological effects of GP-2250 using in vitro and in vivo models.

METHODS: We carried out a series of in vitro (MTT assay, Annexin V/PI assay, colony formation assay, reverse-phase protein array [RPPA], and HRLC/IC analysis) to determine the biological activity of GP-2250 and investigate the mechanism of action. In vivo experiments were carried out to determine the therapeutic efficacy of GP-2250 alone and in combination with …

Autophagic Signaling Promotes Systems-Wide Remodeling In Skeletal Muscle Upon Oncometabolic Stress By D2-Hg, Yaqi Gao, Kyoungmin Kim, Heidi Vitrac, Rebecca L Salazar, Benjamin D Gould, Daniel Soedkamp, Weston Spivia, Koen Raedschelders, An Q Dinh, Anna G Guzman, Lin Tan, Stavros Azinas, David J R Taylor, Walter Schiffer, Daniel Mcnavish, Helen B Burks, Roberta A Gottlieb, Philip L Lorenzi, Blake M Hanson, Jennifer E Van Eyk, Heinrich Taegtmeyer, Anja Karlstaedt

Faculty, Staff and Student Publications

OBJECTIVES: Cachexia is a metabolic disorder and comorbidity with cancer and heart failure. The syndrome impacts more than thirty million people worldwide, accounting for 20% of all cancer deaths. In acute myeloid leukemia, somatic mutations of the metabolic enzyme isocitrate dehydrogenase 1 and 2 cause the production of the oncometabolite D2-hydroxyglutarate (D2-HG). Increased production of D2-HG is associated with heart and skeletal muscle atrophy, but the mechanistic links between metabolic and proteomic remodeling remain poorly understood. Therefore, we assessed how oncometabolic stress by D2-HG activates autophagy and drives skeletal muscle loss.

METHODS: We quantified genomic, metabolomic, and proteomic changes in …

#Hashtagthis – Everything You Need To Know About Launching Your Gynecologic Oncology Social Media Research Career: A Report From Gynecologic Oncology Reports And Society Of Gynecologic Oncology Education Committee, Megan L Hutchcraft, Eric Rios-Doria, Tiffany Y Sia, Eleonora Teplinsky, Shannon N Westin, Gregg Nelson

Faculty, Staff and Student Publications

On February 6th, 2024, Gynecologic Oncology Reports and the Society of Gynecologic Oncology Education Committee co-hosted a webinar about ways to use social media for career enhancement and for dissemination of research. During the discussion, we reviewed:i.how to identify one's goals, target audience, and select a social media platform.ii.how to navigate the negatives of social media.iii.how to develop one's online academic brand.iv.how to use social media for academic promotion and career advancement.v.how to use social media as a research tool.vi.how to use visual tools to bring attention to one's research.The objective of this report is to review the literature on …